Copolymers of tyrosine-based polyarylates and poly(alkylene oxides)

ABSTRACT

Implantable medical devices and drug delivery implants containing polyarylate random block copolymers are disclosed, along with methods for drug delivery and for preventing the formation of adhesions between injured tissues employing the polyarylate random block copolymers.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority benefit under 35U.S.C. §120 of the Nov. 27, 1996 International filing date of co-pendingPCT Application No. PCT/US 96/19098, designating the United States,which in turn claims the priority benefit under 35 U.S.C. §120 from theNov. 27, 1995 filing date of U.S. patent application Ser. No.08/562,842, now U.S. Pat. No. 5,658,995. The disclosures of the PCTApplication and U.S. Pat. No. 5,658,995 are incorporated herein byreference. The present application also claims priority benefit of U.S.Provisional Application Ser. Nos. 60/064,905 filed Nov. 7, 1997 and60/081,502 filed Apr. 13, 1998, the disclosures of both of which arealso incorporated herein by reference thereto. This application alsoclaims priority benefit of U.S. patent application Ser. No. 09/056,050filed Apr. 7, 1998, which, in turn, claims the priority benefit of U.S.Provisional Patent Ser. No. 60/064,656 filed on Nov. 7, 1997. Thedisclosures of both the aforementioned standard U.S. patent applicationand the U.S. provisional patent application from which it claimspriority benefit are also incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to copolymers of tyrosine-basedpolycarbonates and poly(alkylene oxide) and to methods of synthesizingsuch polymers.

[0003] Linear aromatic polycarbonates derived from diphenols such asbisphenol-A represent an important class of condensation polymers. Suchpolycarbonates are strong, tough, high melting materials. They arewell-known in the literature and are commercially produced in largequantities.

[0004] The early investigations on block copolymers of poly(bisphenol-Acarbonate) and poly(alkylene oxide) started in 1961 and were conductedby the groups of Merrill and Goldberg. Merrill, J. Polym. Sci., 55,343-52 (1961) for the first time introduced poly(alkylene oxide) blocksinto poly(bisphenol-A carbonate). Merrill described the interfacialcopolymerization of poly(bisphenol-A carbonate) (dissolved in methylenechloride) and poly(alkylene oxide) bischloroformate (dissolved inaqueous sodium hydroxide). The presence of flexible blocks ofpoly(alkylene oxide) promoted the crystallization of the polycarbonate,which resulted in flexible polymers with high melting points. Later on,Goldberg, J. Polym. Sci., Part C, 4, 707-30 (1964) reported more work onblock copolymers of poly(bisphenol-A carbonate) and poly(ethyleneoxide). The incorporation of flexible, polar, water soluble blocksegments into the rigid, linear, aromatic polycarbonate chains producedelastomers with unusual thermal and plastic properties. In particularGoldberg described the use of poly(ethylene oxide) as a comonomer withbisphenol-A. The synthesis was based on the reaction of phosgene withthe mixture of monomers in pyridine followed by purification of thecopolymer by precipitation in isopropanol. Copolymers were studied forstructure-property correlations as a function of poly(ethylene oxide)molecular weight and copolymer composition. Remarkable strength andsnappy elasticity were observed at poly(ethylene oxide) blockconcentration greater than 3 mole-%. These thermoplastic elastomers alsoexhibited high softening temperatures (>180° C.) and tensile elongationsup to about 700%. Both glass transition temperature and softeningtemperature varied linearly with the molar ratio of poly(ethyleneoxide). The early studies established that these copolymers are goodelastomers, but no medical applications were considered.

[0005] Later on, Tanisugi et al., Polym. J., 17(3), 499-508 (1985);Tanisugi et al., Polym. J., 16(8), 633-40 (1984); Tanisugi et al.,Polym. J., 17(8), 909-18(1984); Suzuki et al., Polym. J., 16(2), 129-38(1983); and Suzuki et al., Polym. J., 15(1), 15-23 (1982) reporteddetailed studies of mechanical relaxation, morphology, water sorption,swelling, and the diffusion of water and ethanol vapors throughmembranes made from the copolymers.

[0006] Mandenius et al., Biomaterials, 12(4), 369-73 (1991) reportedplasma protein absorption of the copolymer, compared to polysulphone,polyamide and polyacrylonitrile as membranes for blood purification.Adhesion of platelets onto Langmuir and solvent cast films of thecopolymers was also reported by Cho et al., J. Biomed. Mat. Res., 27,199-206 (1993). The use of copolymers of poly(bisphenol-A carbonate) andpoly(alkylene oxide) as hemodialysis membrane or plasma separator wasdisclosed in U.S. Pat. Nos. 4,308,145 and 5,084,173 and in EP 46,817; DE2,713,283; DE 2,932,737 and DE 2,932,761.

[0007] Heretofore, block copolymers of polycarbonates and poly(alkyleneoxide) have not been studied as medical implantation materials. Althoughan extensive search of the literature revealed no studies of in vitro orin vivo degradation, one of ordinary skill in the art would not expectthat the currently known block copolymers of poly(bisphenol-A carbonate)and poly(alkylene oxide) would degrade under physiological conditions atrates suitable for the formulation of degradable implants.

[0008] U.S. Pat. Nos. 5,198,507 and 5,216,115 disclosed tyrosine-deriveddiphenolic monomers, the chemical structure of which was designed to beparticularly useful in the polymerization of polycarbonates,polyiminocarbonates and polyarylates. The resulting polymers are usefulas degradable polymers in general, and as tissue compatible bioerodiblematerials for biomedical uses in particular. The suitability of thesepolymers for this end-use application is the result of their derivationfrom naturally occurring metabolites, in particular, the amino acidL-tyrosine.

[0009] Tyrosine-based polycarbonates are strong, tough, hydrophobicmaterials that degrade slowly under physiological conditions. For manymedical applications such as drug delivery, non-thrombogenic coatings,vascular grafts, wound treatment, artificial skin, relatively softmaterials are needed that are more hydrophilic and degrade faster thanthe available tyrosine-based polycarbonates.

SUMMARY OF THE INVENTION

[0010] In this invention, the introduction of poly(alkylene oxide)segments into the backbone of tyrosine-based polycarbonates was found tolead to softer, more hydrophilic polymers that exhibited significantlyincreased rates of degradation. Since the previously known blockcopolymers of poly(bisphenol-A carbonate) and poly(alkylene oxide)apparently do not degrade appreciably under physiological conditions,the finding was unexpected that the incorporation of poly(alkyleneoxide) into tyrosine-based polycarbonate significantly increased therate of degradation. Furthermore, the disclosed copolymers oftyrosine-based polycarbonate and poly(ethylene oxide) have an alkylester pendent chain at each monomeric repeat unit. This pendent chain isan unprecedented structural feature among the currently known blockcopolymers of poly(bisphenol A carbonate) and poly(alkylene oxide). Asshown in more detail below, variation in the length of the pendent chaincan be used to fine-tune the polymer properties. Studies of this kindare known in the literature for other polymer systems, but have not beenperformed for block copolymers of poly(bisphenol A carbonate) andpoly(alkylene oxide). In addition, the presence of a carboxylic acidcontaining pendent chain can facilitate the attachment of biologicallyor pharmaceutically active moieties to the polymer backbone. This, too,is an unprecedented feature among the previously known copolymers ofbisphenol-A and poly(alkylene oxide).

[0011] Therefore, according to one aspect of the present invention, arandom block copolymer of a tyrosine-derived diphenol monomer and apoly(alkylene oxide) is provided having the structure of Formula I:

[0012] wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is zero or aninteger from one to eight;

[0013] R₂ is selected from straight and branched alkyl and alkylarylgroups containing up to 18 carbon atoms and optionally containing atleast one ether linkage and derivatives of biologically andpharmaceutically active compounds covalently bonded to the copolymer;

[0014] each R₃ is independently selected from alkylene groups containingfrom 1 up to 4 carbon atoms;

[0015] y is between about 5 and about 3000; and

[0016] f is the percent molar fraction of alkylene oxide in thecopolymer, and ranges between about 1 and about 99 mole percent.

[0017] Another important phenomena that was observed for the copolymersis the temperature dependent inverse phase transition of the polymer gelor the polymer solution in aqueous solvents. Inverse temperaturetransitions have been observed for several natural and synthetic polymersystems such as proteins and protein-based polymers as described byUrry, Tissue Engineering: Current Perspectives (Boston Birkhauser, NewYork), 199-206, poly(acrylic acid) derived copolymers as described byAnnaka et al., Nature, 355, 430-32(1992); Tanaka et al., Phys. Rev.Lett., 45(20), 1636-39(1980) and Hirokawa et al., J. Chem. Phys.,81(12), 6379-80(1984), and poly(ethylene glycol)-poly(propylene glycol)copolymers as described by Armstrong et al., Macromol. Reports,A31(suppl. 6&7), 1299-306(1994). Polymer gels and solutions of thesepolymers are known to undergo continuous or discontinous volume changeupon changes in temperature, solvent composition, pH or ioniccomposition. The driving forces for the phase change can be attractiveor repulsive electrostatic interactions, hydrogen bonding or hydrophobiceffects.

[0018] For nonionic synthetic polymers such as protein-based bioelasticmaterials, poly(N-isopropylacrylamide) and poly(ethyleneglycol)-poly(propylene glycol) copolymers, as well as the copolymers ofthe present invention, the driving force of phase transition is thecombination of hydrogen bonding and hydrophobic effect. As thetemperature increases, the gels of these polymers undergo a phasetransition from a swollen to a collapsed state, while polymer solutionsprecipitate at certain temperature or within certain temperature ranges.These polymers, including the copolymers of the present invention, andespecially those that undergo a phase transition at about 30-40° C. onheating can be used as biomaterials for drug release and clinicalimplantation materials. Specific applications include the prevention ofadhesions and tissue reconstruction.

[0019] Therefore, the present invention also includes implantablemedical devices containing the random block copolymers of the presentinvention. In one embodiment of the present invention, the copolymersare combined with a quantity of a biologically or pharmaceuticallyactive compound sufficient for therapeutically effective site-specificor systemic drug delivery as described by Gutowska et al., J. Biomater.Res., 29, 811-21 (1995) and Hoffman, J. Controlled Release, 6, 297-305(1987). In another embodiment of the present invention, the copolymer isin the form of a sheet or a coating applied to exposed injured tissuefor use as a barrier for the prevention of surgical adhesions asdescribed by Urry et al., Mat. Res. Soc. Symp. Proc., 292, 253-64(1993).

[0020] Furthermore, another aspect of the present invention provides amethod for site-specific or systemic drug delivery by implanting in thebody of a patient in need thereof an implantable drug delivery devicecontaining a therapeutically effective amount of a biologically orphysiologically active compound in combination with the random blockcopolymer of the present invention. Yet another aspect of the presentinvention provides a method for preventing the formation of adhesionsbetween injured tissues by inserting as a barrier between the injuredtissues a sheet or a coating of the random block copolymer of thepresent invention.

[0021] As noted above, the tyrosine-derived diphenol monomers are alsouseful in the polymerization of polyarylates. The introduction ofpoly(alkylene oxide) segments into the backbone of tyrosine-basedpolyarylates would also be expected to lead to softer, more hydrophilicpolymers with significantly increased rates of degradation. Therefore,according to still yet another aspect of the present invention,aliphatic and aromatic polyarylates are provided, polymerized as randomblock copolymers of a dicarboxylic acid with a tyrosine-derived diphenoland a poly(alkylene oxide), wherein an equimolar combined quantity ofthe diphenol and the poly(alkylene oxide) is reacted with a dicarboxylicacid in a molar ratio of the diphenol to the poly(alkylene oxide)between about 1:99 and about 99:1;

[0022] wherein the tyrosine-derived diphenol has the structure ofFormula II:

[0023] in which R₁ and R₂ are the same as described above with respectto Formula I;

[0024] the dicarboxylic acid has the structure of Formula III:

[0025] in which R is selected from saturated and unsaturated,substituted and unsubstituted alkyl, aryl and alkylaryl groupscontaining up to 18 carbon atoms; and

[0026] the poly(alkylene oxide) has the structure of Formula IV:

(—O—R₃—)_(y)  (IV)

[0027] in which each R₃ is independently selected from alkylene groupscontaining up to 4 carbon atoms and y is between about 5 and about 3000.

[0028] The random block copolymers of the present invention suitable foruse as implantable medical devices, or in methods for site-specific orsystemic drug delivery, or in methods for preventing the formation ofadhesions between injured tissues include the polyarylates of thepresent invention.

[0029] Copolymers based on tyrosine-derived diphenols and poly(alkyleneoxide) represent a new group of nonionic polymers that show inversetemperature transitions. These copolymers contain natural amino acids asbuilding blocks, are degradable under physiological conditions, and havebeen shown to be biocompatible. By changing the tyrosine-deriveddiphenol, the poly(alkylene oxide) and the ratio of the two components,the copolymers can be designed and synthesized to exhibit desiredtransition temperatures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030]FIG. 1 depicts the glass transition temperatures of poly(DTE coPEG_(1,000) carbonates) (O), poly(DTB co PEG_(1,000) carbonates) (Δ) andpoly(DTH co PEG_(1,000) carbonates) (⋄) of the present invention havingdifferent PEG contents and in comparison to corresponding polycarbonatehomopolymers;

[0031]FIG. 2 depicts the water uptake of poly(DTE co 5% PEG_(1,000)carbonate) (o), poly(DTE co 15% PEG_(1,000) carbonate) (⋄) and poly(DTEco 30% PEG_(1,000) carbonate) (Δ) measured as a function of incubationtime at 37° C. in phosphate buffered saline;

[0032]FIG. 3 depicts the pNA release from poly(DTB carbonate) (O),poly(DTB co 1% PEG_(1,000) carbonate) (Δ) and poly(DTB co 5 %PEG_(1,000) carbonate) (⋄) microspheres measured as a function ofincubation time at 37° C. in phosphate buffer;

[0033]FIG. 4 depicts the FITC-dextran released from microspheres made ofpoly(DTB carbonate) (Δ), poly(DTB co 1% PEG_(1,000) carbonate) (⋄) andpoly(DTB co 5% PEG_(1,000) carbonate) (O) as a function of incubationtime at 37° C. in phosphate buffered saline;

[0034]FIG. 5 depicts the molecular weight retention of poly(bisphenol-Aco 5% PEG_(1,000) carbonate) (Δ), poly(DTE co 5% PEG_(1,000) carbonate)(⋄) and poly(DTE co 30% PEG_(1,000) carbonate) (O) as a function ofincubation time at 37° C. in phosphate buffered saline; and

[0035]FIG. 6 depicts a turbidity curve for poly(DTE co 70% PEG_(1,000)carbonate) in water at 500 nm.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0036] The above-defined polymers of Formula I are random blockcopolymers of the above-defined tyrosine-derived diphenols of Formula IIwith the above-defined poly(alkylene oxide) of Formula IV. The definedunits of tyrosine-derived diphenols and poly(alkylene oxide) do notimply the presence of defined blocks within the structure of Formula I.The percent molar fraction of alkylene oxide, f, in the copolymer mayrange between about 1 and about 99 mole percent, with a molar fractionof alkylene oxide between about 5 and about 95 mole percent beingpreferred. The mole percent of alkylene oxide may vary over the entirerange, with polymers having levels of alkylene oxide higher than 5 molepercent being resistant to cell attachment. Polymers with levels higherthan 70 mole percent are water soluble. Polymers with any level ofalkylene oxide are useful, in drug delivery, with water-solublecompositions being preferred for drug-targeting applications.

[0037] The diphenols shown in Formula II are described in co-pending andcommonly owned U.S. patent application Ser. No. 08/414,339 filed Mar.31, 1995. The disclosure of this patent is incorporated herein byreference.

[0038] In Formula II, and thus consequently in Formula I, R₁ ispreferably —CH₂—CH₂— and R₂ is preferably a straight chain ethyl, butyl,hexyl or octyl group. R₂ may contain at least one ether linkage. When R₁is —CH₂—CH₂—, the diphenol compound of Formula I is referred to as adesaminotyrosyl-tyrosine alkyl ester. The most preferred member of thegroup of desaminotyrosyl-tyrosine alkyl esters is the hexyl ester,referred to as desaminotyrosyl-tyrosine hexyl ester or DTH.

[0039] The diphenol compounds may be prepared as described in theabove-referenced U.S. patent application Ser. No. 08/1414,339. Themethod described in U.S. Pat. No. 5,099,060 may also be employed, and isincorporated herein by reference.

[0040] The poly(alkylene oxide) shown in Formula IV can be any commonlyused alkylene oxide known in the art, as is preferably a poly(ethyleneoxide), poly(propylene oxide) or poly(tetra methylene oxide).Poly(alkylene oxide) blocks containing ethylene oxide, propylene oxideor tetramethylene oxide units in various combinations are also possibleconstituents within the context of the current invention.

[0041] The poly(alkylene oxide) is most preferably a poly(ethyleneoxide) in which y of Formula IV is between about 20 and about 200. Morepreferred embodiments are obtained when poly(ethylene oxide) blocks witha molecular weight of about 1,000 to about 20,000 g/mol are used. Forthese preferred embodiments, in the structure of Formula IV, both R₃groups are hydrogen and y has values from about 22 to about 220. A valuefor y ranging between about 22 and about 182 is even more preferred.

[0042] The random block copolymers of Formula I may be prepared by theconventional methods for polymerizing diphenols into polycarbonatesdescribed in the aforementioned U.S. Pat. No. 5,099,060, which methodsare also incorporated herein by reference. This involves the reaction ofthe desired ratio of tyrosine-derived diphenol and poly(alkylene oxide)with phosgene or phosgene precursors (e.g., diphosgene or triphosgene)in the presence of a catalyst. Thus, the copolymers of Formula I may beprepared by interfacial polycondensation, polycondensation in ahomogeneous phase or by transesterification. The suitable processes,associated catalysts and solvents are known in the art and are taught inSchnell, Chemistry and Physics of Polycarbonates, (Interscience, NewYork 1964), the teachings of which are also incorporated herein byreference. One of ordinary sill in the art will be able to extend thedisclosed techniques to the random block copolymerization of atyrosine-derived diphenol with a poly(alkylene oxide) without undueexperimentation.

[0043] The random block copolymers of Formula I have weight-averagemolecular weights above about 20,000 daltons, and preferably above about30,000 daltons. The number-average molecular weights of the random blockcopolymers of Formula I are above about 10,000 daltons, and preferablyabove about 20,000 daltons. Molecular weight determinations arecalculated from gel permeation chromatography relative to polystyrenestandards without further correction.

[0044] As disclosed above, R₂ of the random block copolymer of Formula Iand the tyrosine-derived diphenol of Formula II can be a derivative of abiologically or pharmaceutically active compound covalently bonded tothe copolymer or diphenol. R₂ is covalently bonded to the copolymer ordiphenol by means of an amide bond when in the underivatizedbiologically or pharmaceutically active compound a primary or secondaryamine is present at the position of the amide bond in the derivative. R₂is covalently bonded to the copolymer or diphenol by means of an esterbond when in the underivatized biologically or pharmaceutically activecompound a primary hydroxyl is present at the position of the ester bondin the derivative. The biologically or pharmaceutically active compoundmay also be derivatized at a ketone, aldehyde or carboxylic acid groupwith a linkage moiety that is covalently bonded to the copolymer ordiphenol by means of an amide or ester bond.

[0045] Examples of biologically or pharmaceutically active compoundssuitable for use with the present invention include acyclovir,cephradine, malphalen, procaine, ephedrine, adriamycin, daunomycin,plumbagin, atropine, quinine, digoxin, quinidine, biologically activepeptides, chlorin e₆, cephradine, cephalothin, melphalan, penicillin V,aspirin, nicotinic acid, chemodeoxycholic acid, chlorambucil, and thelike. The compounds are covalently bonded to the copolymer or diphenolby methods well understood by those of ordinary skill in the art. Drugdelivery compounds may also be formed by physically blending thebiologically or pharmaceutically active compound to be delivered withthe random block copolymers of the present invention using conventionaltechniques well-known to those of ordinary skill in the art.

[0046] The tyrosine-derived diphenol compounds of Formula II and thepoly(alkylene oxide) of Formula IV may also be reacted according to themethod disclosed by U.S. Pat. No. 5,216,115 to form polyarylates, thedisclosure of which is hereby incorporated by reference thereto. Asdisclosed by U.S. Pat. No. 5,216,115, the diphenol compounds are reactedwith the aliphatic or aromatic dicarboxylic acids of Formula III in acarbodiimide mediated direct polyesterification using4-(dimethylamino)pyridinium-p-toluene sulfonate (DPTS) as a catalyst toform aliphatic or aromatic polyarylates. Random block copolymers withpoly(alkylene oxide) may be formed by substituting poly(alkylene oxide)for the tyrosine derived diphenol compound in an amount effective toprovide the desired ratio of diphenol to poly(alkylene oxide) in therandom block copolymer.

[0047] The random block copolymers of the present invention, bothpolycarbonate and polyarylates, can be worked up by known methodscommonly employed in the field of synthetic polymers to produce avariety of useful articles with valuable physical and chemicalproperties, all derived from tissue-compatible monomers. The usefularticles can be shaped by conventional polymer-forming techniques suchas extrusion, compression molding, injection molding, solvent casting,spin casting, and the like. Shaped articles prepared from the polymersare useful, inter alia, as degradable biomaterials for medical implantapplications. Such applications include the use of the shaped articlesas vascular grafts and stents, bone plates, sutures, implantablesensors, barriers for surgical adhesion prevention, implantable drugdelivery devices, scaffolds for tissue regeneration, and othertherapeutic aids and articles which decompose harmlessly within a knownperiod of time. The polymers can also be formed as a coating on thesurface of implants by conventional dipping or spray coating techniquesto prevent the formation of adhesions on the implant.

[0048] Implantable articles formed from the random block copolymers ofthe present invention must be sterile. Sterility is readily accomplishedby conventional methods such as irradiation or treatment with gases orheat.

[0049] The following non-limiting examples set forth hereinbelowillustrate certain aspects of the invention. All parts and percentagesare by weight unless otherwise noted and all temperatures are in degreesCelsius.

[0050] MATERIALS AND METHODS

[0051] Materials

[0052] L-Tyrosine, thionyl chloride, pyridine, methylene chloride,tetrahydrofuran (THF), ethanol, butanol, hexanol, octanol,3-(4-hydroxy-phenyl)propionic acid (desaminotyrosine, Dat), dicyclohexylcarbodiimide (DCC), and hydroxybenzotriazole (HOBt) were obtained fromAldrich, phosgene (solution in toluene) was obtained from Fluka. Allsolvents were of HPLC grade and were used as received.

[0053] Spin Casting

[0054] The bottom glass slide of dual chamber units (#177380, Nunc,Inc.) was spin cast first with a styrene silane copolymer solution (2.5%w/v in ethyl acetate), as described by Ertel et al., J. Biomat. Sci.Polym. Edn., 3, 163-83 (1991), which served as a coupling agent, andthen with the polymer solution (2% w/v in methylene chloride) for 30 sat 800 rpm. The coated slides were dried under vacuum for one week priorto cell culture. Poly(bisphenol-A carbonate) was similarly spin cast andincluded as a control in the cell growth studies.

[0055] Compression Molding

[0056] Thin polymer films were prepared by compression molding.Processing temperature was 30-35° C. above Tg for each polymer. Tominimize polymer adhesion to the metal plates of the mold, two teflonsheets were added between the polymer and metal plates of the mold.

[0057] Spectroscopy

[0058] FT-IR spectra were recorded on a Matson Cygnus 100 spectrometer.Polymer samples were dissolved in methylene chloride and films were castdirectly onto NaCl plates. All spectra were collected after 16 scans at2 cm⁻¹ resolution. UV/Vis spectra were recorded on a Perkin-Elmer Lambda3B spectrophotometer. NMR spectra of polymer solutions in deuteratedchloroform were recorded on a Varian VXR-200 spectrometer (64 scans).

[0059] Gel Permeation Chromatography (GPC)

[0060] The chromatographic system consisted of a Perkin-Elmer Model 410pump, a Waters Model 410 RI detector, and a PE-Nelson Model 2600computerized data station. Two PL-gel GPC columns (pore size 10⁵ and 10³Å) were operated in series at a flow rate of 1 ml/min using THF.Molecular weights were calculated relative to polystyrene standardswithout further correction.

[0061] Thermal Analysis

[0062] The glass transition temperature (T_(g)) was determined bydifferential scanning calorimetry (DSC) on a DuPont 910 DSC instrumentcalibrated with indium. Each specimen was subjected to two consecutiveDSC scans. After the first run the specimen was quenched with liquidnitrogen and the second scan was performed immediately thereafter.T_(g)was determined in the second DSC scan as the midpoint. The heatingrate for all polymers was 10° C./min and the average sample size was 10mg.

[0063] Water Uptake

[0064] A piece of copolymer (15-20 mg) was cut from a film incubated inPBS at 37° C., and wiped to remove water on the surface of the sample.Water content (WC in %) was determined by thermogravimetric analysis(TGA) on a DuPont 951 TGA instrument at a heating rate of 10° C./min andwas reported as percentage weight lost below 200° C. Water uptake wascalculated as WC/(1−WC).

[0065] Hydrolytic Degradation Studies

[0066] Samples were cut from compression molded films and incubated at37° C in phosphate buffer saline (0.1 M, pH 7.4) (PBS) containing 200mg/L of sodium azide to inhibit bacterial growth. The degradationprocess was followed by recording weekly the changes in the molecularweight of the polymer. Results are the average of two separate specimensper polymer.

[0067] Microsphere Processing

[0068] Microspheres were prepared by solvent evaporation as described byMathiowitz et al., J. App Polym. Sci., 35, 755-74 (1988). 0.05 g ofcopolymer was dissolved in 1 mL of methylene chloride. The polymersolution was injected into 50 mL of an aqueous solution of poly(vinylalcohol) (PVA) in a 150 mL beaker with 3 baffles. The mixture wasstirred by a overhead stirrer with a propeller at 1300 rpm. After 4 h ofstirring, the microspheres were collected by membrane filtration andwashed 6 times with water to remove as much PVA as possible. Then themicrospheres were dried to constant weight under high vacuum.

[0069] Drug Loading and Release

[0070] p-Nitroaniline (pNA) was dissolved in the polymer solutionfollowed by microsphere formation as described above. pNA loading wasdetermined by UV spectroscopy (λ=380 nm) after complete dissolution ofan exactly weighed amount of microspheres in methylene chloride.

[0071] FITC-dextrans were dissolved in 50 ml of water and dispersed inthe polymer solution by sonication (w/o/w method) followed bymicrosphere formation as described above. To determine the FITC-dextranloading, the microspheres were dissolved in methylene chloride and theFITC-dextran was extracted into aqueous phosphate buffer solution (0.1M, pH 7.4) followed by florescence spectrophotometry (excitation: 495nm, emission: 520 nm).

[0072] An exactly weighed amount of pNA or FITC-dextran loadedmicrospheres were placed in an exactly measured volume of phosphatebuffer solution (0.1 M, pH 7.4) at 37° C. in a water shaker bath. Theamount of pNA or FITC-dextran released into the buffer solution wasdetermined as described above.

[0073] Cell Growth

[0074] Fetal rat lung fibroblasts (#CCL192, American Tissue CultureCollection) were grown in Ryan Red medium with 50 mg/ml sodium ascorbateand 10% fetal calf serum as described by Poiani et al., Amino Acids, 4,237-48 (1993) and Ryan et al., Tiss. Cult. Meth., 10, 3-5 (1986). Forpolymer evaluation, the dual chamber units (#177380, Nunc, Inc.) werespin cast first with a styrene silane copolymer solution (2.5% w/v inethyl acetate), which served as a coupling agent, and then with thepolymer solution of interest. Unmodified plastic (#177429, Nunc) andglass dual chamber units (#177380, Nunc) served as controls and wereused as received. Prior to cell seeding, all surfaces were incubated for3 hours with PBS containing 5 % penicillin-streptomycin. Cells frompassage 5 were subsequently seeded at a density of 10⁴ cells/cm^(2.)After 1 or 5 days of incubation, the cells were gently rinsed with PBS,and trypsinized from 3 separate chambers. The suspension was counted 4times in a hemocytometer.

[0075] Measurement of Inverse Temperature Transition

[0076] The detection of inverse phase transition is based on theincrease in turbidity as the initial soluble polymerprecipitates uponheating. The increase in turbidity is monitored by visible spectroscopyas described below.

[0077] Polymer solutions: Optical Density (OD) measurements for 0.05%(w/v) polymer aqueous solutions were performed at 500 nm on a diodearray spectrophotomer (Hewlett Packard, Model 8452-A) with awater-jacketed cell holder coupled with a refrigerated circulating bath(Neslab, model RTE-8). Temperature was manually controlled at rates of0.5° C./min. and monitored by a microprocessor thermometer (Omega, modelHH22). The initial breaking point in the resulting optical densityversus temperature curve was taken as the onset of the temperature oftransition.

[0078] Nomenclature

[0079] Copolymer structure and composition is represented in thefollowing way: in poly(DTX co fPEG_(Mw) carbonate), X relates to thelength of the alkyl ester pendent chain. In the examples described belowE (ethyl), B (butyl), and H (hexyl) were used. The percent molarfraction of poly(ethylene oxide) content in the copolymer is representedby the letter f. In the samples listed below, the value of f was variedfrom 1 to 70 mole%. M_(w) represents the average molecular weight of thePEG blocks used in the synthesis of the copolymer. Thus, Poly (DTE co 5%PEG_(1,000) carbonate) refers to a copolymer prepared from the ethylester of desaminotyrosyl-tyrosine, and 5 mole % of PEG blocks having anaverage molecular weight of 1000 g/mol.

EXAMPLES Example 1

[0080] Poly(DTE co 5% PEG_(1,000) carbonate) was synthesized as follows:

[0081] 10.85 g of DTE (30.4 mmole) and 1.57 g of PEG_(1,000) (1.59mmole) were placed into a 250 ml flask. Then 60 ml of dry methylenechloride and 9.6 ml of anhydrous pyridine were added. At roomtemperature, 20.6 ml of a 1.93 M solution of phosgene in toluene wasadded slowly to the solution with overhead stirring during 90 minutes.180 ml THF was added to dilute the reaction mixture. The copolymer wasprecipitated by slowly adding the mixture into 2400 ml of ethyl ether.The copolymer was redissolved in 220 ml THF (5% w/v solution) andreprecipitated by slowly adding the polymer solution into 2200 ml ofwater.

[0082] 10.8 g of a white copolymer was obtained. As determined by GPCusing THF as the solvent, the copolymer has a weight average molecularweight of 127,000 daltons, a number average molecular weight of 84,000daltons and a polydispersity of 1.5.

Example 2

[0083] Poly(DTE co 30% PEG_(1,000) carbonate) was synthesized asfollows:

[0084] 5.23 g of DTE (14.6 mmole) and 6.20 g of PEG_(1,000) (6.27 mmole)were placed into a 250 ml flask. Then 60 ml of dry methylene chlorideand 6.7 ml of anhydrous pyridine were added. At room temperature, 13.5ml of a 1.93 M solution of phosgene in toluene was added slowly to thesolution with overhead stirring during 90 minutes. 180 ml THF was addedto dilute the reaction mixture. The copolymer was precipitated by slowlyadding the mixture into 2400 ml of ethyl ether. The copolymer wasredissolved in 200 ml THF (5% w/v solution) and reprecipitated by slowlyadding the polymer solution into 2000 ml of water.

[0085] 8.9 g of a white copolymer was obtained. As determined by GPCusing THF as the solvent, the copolymer has a weight average molecularweight of 41,000 daltons, a number average molecular weight of 31,000daltons and a polydispersity of 1.3.

Example 3

[0086] Poly(DTO co 5% PEG_(1,000) carbonate) was synthesized as follows:

[0087] 9.23 g of DTO (20.9 mmole) and 1.09 g of PEG_(1,000) (1.1 mmole)were placed into a 250 ml flask. Then 50 ml of dry methylene chlorideand 7.0 ml of anhydrous pyridine were added. At room temperature, 14.3ml of a 1.93 M solution of phosgene in toluene was added slowly to thesolution with overhead stirring during 90 minutes. 150 ml ThF was addedto dilute the reaction mixture. The copolymer was precipitated by slowlyadding the mixture into 2000 ml of ethyl ether. The copolymer wasredissolved in 200 ml THF (5% w/v solution) and reprecipitated by slowlyadding the polymer solution into 2000 ml of water.

[0088] 9.1 g of a white copolymer was obtained. As determined by GPCusing ThF as the solvent, the copolymer has a weight average molecularweight of 32,000 daltons, a number average molecular weight of 13,000daltons and a polydispersity of 2.5.

Example 4

[0089] Poly(DTE co 0.262% PEG_(20,000) carbonate) was synthesized asfollows:

[0090] 10.24 g of DTE (28.6 mmole) and 1.5 g of PEG_(20,000) (0.075mmole) were placed into a 250 ml flask. Then 60 ml of dry methylenechloride and 8.7 ml of anhydrous pyridine were added. At roomtemperature 18.6 ml of a 1.93 M solution of phosgene in toluene wasadded slowly to the solution with overhead stirring during 90 minutes.180 ml THF was added to dilute the reaction mixture. The copolymer wasprecipitated by slowly adding the mixture into 2400 ml of ethyl ether.The copolymer was redissolved in 220 ml THF (5% w/v solution) andreprecipitated by slowly adding the polymer solution into 2200 ml ofwater.

[0091] 10.1 g of a white copolymer was obtained. As determined by GPCusing THF as the solvent, the copolymer has a weight average molecularweight of 178,000 daltons, a number average molecular weight of 84,000daltons and a polydispersity of 2.1.

Example 5

[0092] Poly(DTE co 70% PEG_(1,000) carbonate) is water soluble, so inthe final purification step, isopropanol was used instead of water:

[0093] 1.29 g of DTE (3.60 mmole) and 8.31 g of PEG_(1,000) (8.40 mmole)were placed into a 250 ml flask. Then 50 ml of dry methylene chlorideand 3.6 ml of anhydrous pyridine were added. At room temperature, 7.8 mlof a 1.93 M solution of phosgene in toluene was added slowly to thesolution with overhead stirring during 90 minutes. 150 ml THE was addedto dilute the reaction mixture. The copolymer was precipitated by slowlyadding the mixture into 2000 ml of ethyl ether. The copolymer wasredissolved in 70 ml THF (5% w/v solution) and reprecipitated by slowlyadding the polymer solution into 700 ml of isopropanol.

[0094] 6.4 g of a white copolymer was obtained. As determined by GPCusing THF as the solvent, the copolymer has a weight average molecularweight of 47,000 daltons, a number average molecular weight of 37,000daltons and a polydispersity of 1.3.

[0095] Poly(DTB co 1% PEG_(1,000) carbonate), Poly(DTB co 5% PEG_(1,000)carbonate), Poly(DTB co 10% PEG_(1,000) carbonate), Poly(DTH co co 1%PEG_(1,000) carbonate), Poly(DTH co 5% PEG_(1,000) carbonate), Poly(DTHco 10% PEG_(1,000) carbonate), Poly(DTH co 20% PEG_(1,000) carbonate)and poly(bisphenol-A co 5% PEG_(1,000) carbonate) were synthesized bysimilar methods and used for different studies.

Polymer Characterization

[0096] Glass transition temperature

[0097] Copolymers were prepared according to the examples given above.The glass transition temperature (T_(g)) of these copolymers and theircorresponding polycarbonate homopolymers were measured (FIG. 1). In eachseries of copolymers, T_(g)of the copolymers decreased as the molarfraction of PEG_(1,000) increased.

[0098] Mechanical Properties

[0099] Tensile modulus: The dry specimens of poly(DTE co 5% PEG_(1,000)carbonate) had tensile modulus of 1.3 Gpa, which is comparable to alltyrosine-derived polycarbonates which have tensile modulus within arange of 1.2-1.6 Gpa. See Ertel et al., J. Biomed. Mater. Res., 28,919-930 (1994). After 24 h of incubation, the specimens had 10% of wateruptake, and the tensile modulus dropped to 0.58 Gpa.

[0100] Tensile strength at yield and break: The combination of PEG intothe backbone of the tyrosine derived polymer had a profound effect onthe tensile strength and ductility of the polymer. While poly(DTEcarbonate) was very brittle and failed without yielding after 4%elongation (See the aforementioned Ertel et. al., J. Biomed. Mater.Res., 28, 919-930 (1994)), the poly(DTE co 5% PEG_(1,000) carbonate) didmanage to elongate up to 153% before failing. The tensile strength atyield was 41 MPa, at break was 22 MPa. The incubated copolymer becameextremely ductile. Film specimens yielded after 6% elongation and failedafter up to 650% elongation. The tensile strength at yield was 15 MPa,at break was 19 MPa.

[0101] Water Uptake

[0102] The amount of water taken up by thin, compression molded films ofpoly(DTE co PEG_(1,000) carbonates) was determined as described in theexperimental section. The compression molded test specimens contained 5mol %, 15 mol %, or 30 mol % of PEG. Over a 5 h period, poly(DTE co 5%PEG_(1,000) carbonate) reached an equilibrium water uptake of 10%. Forpoly(DTE co 15% PEG_(1,000) carbonate), the equilibrium water uptakeafter 1 h was 25%. For poly(DTE co 30% PEG_(1,000) carbonate) theequilibrium water uptake after only 1 h was 92%. The rate of wateruptake and the equilibrium water content increased as the molar fractionof poly(ethylene oxide) increased (FIG. 2). At poly(ethylene oxide)contents above 20%, the copolymers behave increasingly like hydrogels.

[0103] Microsphere Formation and Drug Release

[0104] The formation of microspheres was studied using poly(DTB coPEG_(1,000) carbonates). The homopolymer, poly(DTB carbonate) wasincluded in the studies as control. Next, microspheres were formulatedcontaining either pNA or FITC-dextran. These compounds are useful modelsfor low molecular weight hydrophobic drugs and high molecular weighthydrophilic drugs respectively. As a general rule, microspheres couldonly be isolated when the PEG content was below 10%. Above that value,microspheres formed initially, but tended to adhere to each other andformed a gum-like precipitate during work up. Thus, free flowingmicrospheres were formed for the poly(DTB carbonate) and for poly(DTB co1% PEG_(1,000) carbonate) and poly(DTB co 5% PEG₁₀₀₀ carbonate). Forpoly(DTB co10% PEG_(1,000) carbonate), no microspheres could beisolated.

[0105] It was an unexpected finding that the presence of even very smallmolar fractions of poly(alkylene oxide) had a significant effect on thedrug release rate. This is illustrated in FIG. 3, showing the cumulativerelease of pNA from the series of copolymers of DTB and PEG₁₀₀₀.

[0106] The release of FITC-dextran from microspheres made of thehomopolymers was extremely slow. The typical release profile forFTIC-dextran from the homopolymers was characterized by a short bursteffect followed by a very long lag period during which no furtherFITC-dextran was released from the microspheres. Including 1 to 5% ofPEG_(1,000) in the polymer composition led to a significant increase inthe amount of FITC-dextran that was rapidly released from themicrospheres (FIG. 4). Thus, the disclosed copolymers can assist in theformulation of controlled drug release systems for hydrophilic, highmolecular weight drugs.

[0107] Degradation in Vitro

[0108] Degradation study was performed for two poly(DTE co PEG_(1,000)carbonates) with poly(bisphenol-A co 5% PEG_(1,000) carbonate) ascontrol. After one day of incubation in buffer at 37° C., thin filmspecimens of all copolymers had adsorbed water and reached saturation.Contrary to the industrially used very slowly degrading poly(bisphenol-Aco PEG carbonates) the tyrosine-derived poly(DTX co PEG carbonates)degraded fast under physiological conditions in vitro, as demonstratedby GPC.

[0109] The changes in the molecular weight over time were followed forall three polymers. When the changes were plotted as percent molecularweight retention vs. time, all three polymers had similar degradationprofiles, shown for poly(bisphenol-A co 5% PEG_(1,000) carbonate),poly(DTE co 5% PEG_(1,000) carbonate) and poly(DET co. 30% PEG_(1,000)carbonate) in FIG. 5. During nine weeks of observation, poly(bisphenol-Aco 5% PEG_(1,000) carbonate) lost only about 15% of its molecular weightwhile poly(DTE co 5% PEG_(1,000) carbonate) and poly(DTE co 30%PEG_(1,000) carbonate) lost about 60% and 75% of their molecular weight.

[0110] Inverse Temperature Transition

[0111]FIG. 6 illustrates the inverse temperature transition for poly(DTECo 70% PEG_(1,000) carbonate). This polymer is initially in solution asshown by its low absorbence at 500 nm. Upon heating, the polymerprecipitates, as indicated by the increasing absorbance. In thisparticular case, the phase transition starts at 57±1° C.

[0112] Cell Growth

[0113] The interactions of the polymer with living cells providesimportant information about possible medical applications. In vitrostudies of cell growth also provide an indication of the possiblecytotoxicity of a polymer. Such studies are recognized as the firstscreening tests in the biocompatibility evaluation of medical implantmaterials according to the FDA Tripartide Biocompatibility guidelines.

[0114] Cell growth and spreading decreased as the molar fraction of PEGpresent in the copolymer increased (Table I). This can be explained byreduced cellular attachment due to the high mobility of the PEG block onthe polymer surface. An alternative explanation is based on the generaltendency of PEG to prevent the adsorption of proteins onto surfaces.Thus, when PEG is part of the polymer structure, less proteins may beadsorbed to the polymer surface which, in turn, reduces the ability ofcells to attach to the surface. It was an unexpected finding that aslittle as 5% of PEG_(1,000) in the copolymer was sufficient to eliminatealmost completely the ability of rat lung fibroblasts cells to attachand grow on the copolymer surfaces. The unattached cells float in themedium and aggregate to each other. Viability tests using trypan blueand calcein AM show that these cells remain viable even after 5 days.This demonstrated that the copolymers are non-cytotoxic. TABLE I CellAttachment And Proliferation On Surfaces Of Copolymers AttachmentProliferation PEG Copolymer (× 100 cell/cm²) Diphenol Mole % PEG 1 day 5days DTE  0 46 ± 13 596 ± 100  5 8 ± 8 46 ± 14 15 4 ± 5 11 ± 10 30 3 ± 511 ± 10 DTB  0 56 ± 17 401 ± 79   1 50 ± 14 163 ± 40   5 16 ± 10 18 ± 1310 9 ± 9 7 ± 7 DTH  0 32 ± 10 268 ± 46   1 52 ± 31 275 ± 71   5  9 ± 113 ± 7 10  9 ± 11 11 ± 14 Control surfaces glass 50 ± 16 555 ± 91 poly(BPA carbonate) 17 ± 10 123 ± 37 

[0115] The foregoing examples and description of the preferredembodiment should be taken as illustrating, rather than as limiting, thepresent invention as defined by the claims. As will be readilyappreciated, numerous variations and combinations of the features setforth above can be utilized without departing from the present inventionas set forth in the claims. Such variations are not regarded as adeparture from the spirit and scope of the invention, and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is
 1. An implantable medical device comprising apolyarylate, polymerized as a random block copolymer of a dicarboxylicacid with both a tyrosine-derived diphenol and a poly(alkylene oxide),wherein an equimolar combined quantity of said diphenol and saidpoly(alkylene oxide) is reacted with said dicarboxylic acid in a molarratio of said diphenol to said poly(alkylene oxide) between about 1:99and about 99:1; and wherein said dicarboxylic acid has the structure:

in which R is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; said tyrosine derived diphenolhas the structure:

in which R₁ is —CH═CH— or (—CH₂—)_(j), wherein j is zero or an integerfrom one to eight, and R₂ is selected from the group consisting ofstraight and branched alkyl and alkylaryl groups containing up to 18carbon atoms and optionally containing at least one ether linkage andderivatives of biologically and pharmaceutically active compoundscovalently bonded to said diphenol; and said poly(alkylene oxide) hasthe structure: (—O—R₃—)_(y) in which each R₃ is independently analkylene group containing up to 4 carbon atoms and y is an integerbetween about 5 and about
 3000. 2. The implantable medical device ofclaim 1 , wherein the surface of said device is coated with said randomblock copolymer.
 3. The implantable medical device of claim 1 ,comprising a biologically or physiologically active compound incombination with said random block copolymer, wherein said activecompound is present in an amount sufficient for therapeuticallyeffective site-specific or systemic drug delivery.
 4. The implantablemedical device of claim 3 , wherein said biologically or physiologicallyactive compound is covalently bonded to said copolymer.
 5. Animplantable medical device in the form of a sheet consisting essentiallyof a polyarylate, polymerized as a random block copolymer of adicarboxylic acid with both a tyrosine-derived diphenol and apoly(alkylene oxide), wherein an equimolar combined quantity of saiddiphenol and said poly(alkylene oxide) is reacted with said dicarboxylicacid in a molar ratio of said diphenol to said poly(alkylene oxide)between about 1:99 and about 99:1; and wherein said dicarboxylic acidhas the structure:

in which R is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; said tyrosine-derived diphenolhas the structure:

in which R₁ is —CH═CH— or (—CH₂—)_(j), wherein j is zero or an integerfrom one to eight, and R₂ is selected from the group consisting ofstraight and branched alkyl and alkylaryl groups containing up to 18carbon atoms and optionally containing at least one ether linkage andderivatives of biologically and pharmaceutically active compoundscovalently bonded to said diphenol; and said poly(alkylene oxide) hasthe structure: (—O—R₃—)_(y) in which each R₃ is independently analkylene group containing up to 4 carbon atoms and y is an integerbetween about 5 and about
 3000. for use as a barrier for surgicaladhesion prevention.
 6. A method for site-specific or systemic drugdelivery comprising implanting in the body of a patient in need thereofan implantable drug delivery device comprising a therapeuticallyeffective amount of a biologically or physiologically active compound incombination with a polyarylate, polymerized as a random block copolymerof a dicarboxylic acid with both a tyrosine-derived diphenol and apoly(alkylene oxide), wherein an equimolar combined quantity of saiddiphenol and said poly(alkylene oxide) is reacted with said dicarboxylicacid in a molar ratio of said diphenol to said poly(alkylene oxide)between about 1:99 and about 99:1; and wherein said dicarboxylic acidhas the structure:

in which R is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; said tyrosine-derived diphenolhas the structure:

in which R₁ is —CH═CH— or (—CH₂—)_(j), wherein j is zero or an integerfrom one to eight, and R₂ is selected from the group consisting ofstraight and branched alkyl and alkylaryl groups containing up to 18carbon atoms and optionally containing at least one ether linkage andderivatives of biologically and pharmaceutically active compoundscovalently bonded to said diphenol; and said poly(alkylene oxide) hasthe structure: (—O—R₃—)_(y) in which each R₃ is independently analkylene group containing up to 4 carbon atoms and y is an integerbetween about 5 and about
 3000. 7. The method of claim 6 , wherein saidbiologically or physiologically active compound is covalently bonded tosaid copolymer.
 8. A method for preventing the formation of adhesionsbetween injured tissues comprising inserting as a barrier between saidinjured tissues a sheet consisting essentially of a polyarylate,polymerized as a random block copolymer of a dicarboxylic acid with botha tyrosine-derived diphenol and a poly(alkylene oxide), wherein anequimolar combined quantity of said diphenol and said poly(alkyleneoxide) is reacted with said dicarboxylic acid in a molar ratio of saiddiphenol to said poly(alkylene oxide) between about 1:99 and about 99:1;and wherein said dicarboxylic acid has the structure:

in which R is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; said tyrosine-derived diphenolhas the structure:

in which R₁ is —CH═CH— or (—CH₂—)_(j), wherein j is zero or an integerfrom one to eight, and R₂ is selected from the group consisting ofstraight and branched alkyl and alkylaryl groups containing up to 18carbon atoms and optionally containing at least one ether linkage andderivatives of biologically and pharmaceutically active compoundscovalently bonded to said diphenol; and said poly(alkylene oxide) hasthe structure: (—O—R₃—)_(y) in which each R₃ is independently analkylene group containing up to 4 carbon atoms and y is an integerbetween about 5 and about
 3000. 9. The controlled drug delivery systemcomprising a biologically or pharmaceutically active compound physicallycoated with a random block copolymer having the formula:

wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is zero or an integerfrom one to eight; R₂ is selected from the group consisting of straightand branched alkyl and alkylaryl groups containing up to 18 carbon atomsand optionally containing at least one ether linkage, and derivatives ofbiologically and physiologically active compounds covalently bonded tosaid copolymer; each R₃ is independently an alkylene group containing upto 4 carbon atoms; A is selected from the group consisting of:

wherein R₈ is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; y is between about 5 and about3000; and f is the percent molar fraction of alkylene oxide in saidcopolymer and ranges between about 1 and about 99 mole percent.
 10. Acontrolled drug delivery system comprising a random block copolymerhaving the formula:

wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is zero or an integerfrom one to eight; R₂ is selected from the group consisting of straightand branched alkyl and alkylaryl groups containing up to 18 carbon atomsand optionally containing at least one ether linkage, and derivatives ofbiologically and physiologically active compounds covalently bonded tosaid copolymer; each R₃ is independently an alkylene group containing upto 4 carbon atoms; A is selected from the group consisting of:

wherein R₈ is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; y is between about 5 and about3000; and f is the percent molar fraction of alkylene oxide in saidcopolymer and ranges between about 1 and about 99 mole percent.Physically add mixed with a biologically or pharmaceutically activecompound.
 11. A controlled drug delivery system comprising abiologically or pharmaceutically active compound physically embedded ordispersed into a polymeric matrix formed from a random block copolymerhaving the formula:

wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is zero or an integerfrom one to eight; R₂ is selected from the group consisting of straightand branched alkyl and alkylaryl groups containing up to 18 carbon atomsand optionally containing at least one ether linkage, and derivatives ofbiologically and physiologically active compounds covalently bonded tosaid copolymer; each R₃ is independently an alkylene group containing upto 4 carbon atoms; A is selected from the group consisting of:

wherein R₈ is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; y is between about 5 and about3000; and f is the percent molar fraction of alkylene oxide in saidcopolymer and ranges between about 1 and about 99 mole percent.
 12. Amethod of regulating cellular attachment, migration and proliferation ona polymeric substrate, comprising contacting living cells, tissues orbiological fluids containing living cells with a random block copolymerhaving the formula:

wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is zero or an integerfrom one to eight; R₂ is selected from the group consisting of straightand branched alkyl and alkylaryl groups containing up to 18 carbon atomsand optionally containing at least one ether linkage, and derivatives ofbiologically and physiologically active compounds covalently bonded tosaid copolymer; each R₃ is independently an alkylene group containing upto 4 carbon atoms; A is selected from the group consisting of:

wherein R₈ is selected from the group consisting of saturated andunsaturated, substituted and unsubstituted alkyl, aryl and alkylarylgroups containing up to 18 carbon atoms; y is between about 5 and about3000; and f is the percent molar fraction of alkylene oxide in saidcopolymer and ranges between about 1 and about 99 mole percent.
 13. Themethod of claim 12 , wherein said polymer is in the form of a coating ona medical implant.
 14. The method of claim 12 , wherein said polymer isin the form of a film.
 15. The method of claim 12 , wherein said polymeris in the form of a polymeric tissue scaffold.